This invention relates to novel 1,4-dihydropyridine compounds. These compounds are useful as antagonists of bradykinin, and are thus useful in the treatment of inflammation, cardiovascular disease or the like in mammalian, especially humans. The present invention also relates to a pharmaceutical composition comprising the above compounds.
Bradykinin (xe2x80x9cBKxe2x80x9d) is generated under normal conditions in mammalia by the action of various plasma enzymes such as kallikrein on high molecular weight kininogens. It is widely distributed in mammals, as are its two receptor subtypes, B1 and B2. The actions of BK at the B2 receptor include mainly contraction of arterial and venous preparations, although it can cause relaxation of peripheral resistance vessels as well.
Many of the more important functions of BK, such as increases in vascular permeability, pain, and vasodilatation, however, are mediated by the B2 receptor. These effects at the B2 receptor are believed to be responsible for BK""s role in numerous diseases, such as inflammation, cardiovascular disease, pain, and the common cold. Hence antagonists at the B2 receptor should find considerable therapeutic applications. Most of the efforts in this area thus far have been directed at peptidic analogues of the BK structure, some of which have been studied as analgesics and antiinflammatory agents.
International Publication Number WO 96/06082 discloses a variety of 1,4-dihydropyridine compounds having a piperazinylcarbonylmethy group at the 2-position, as antagonists of bradykinin.
It would be desirable if there were provided a non-peptide antagonist of the B2 receptor, having an improved B2 antagonistic activity and a good metabolic stability against human liver microsomes.
The present invention provides a compound of the following formula: 
or the pharmaceutically acceptable salts thereof wherein
A is independently halo;
Y1 is xe2x80x94(CH2)mxe2x80x94, C(O) or S(O);
Y2 is N or CH;
R1 and R2 are independently C1-4 alkyl;
R3 is selected from the following:
(a) xe2x80x94(CH2)pxe2x80x94C3-7 cycloalkyl, the cycloalkyl moiety being optionally substituted with one, two or three substituents selected from cyano, amino-C1-4 alkyl-, C1-4 alkylamino-C1-4 alkyl-, C1-3 alkyl-carbonylamino-C1-4 alkyl-, C1-4 alkylsulfonylamino-C1-4 alkyl, amino, 2-oxopyrrolidinyl, C4-7 cycloalkylamino-C1-4 alkyl, di-C1-4 alkylamino-C1-4 alkyl-, hydroxyl, carbamoyl, C1-3 alkylcarbonyl(C1-4 alkyl)amino, C1-4 alkylcarbonyl(C1-4 alkyl)amino-C1-4 alkyl, di-C1-4 alkylamino, pyrrolidinyl-C1-4 alkyl, 2-oxopyrrolidinyl-C1-4 alkyl and di-C1-4 alkylamino-C1-4 alkyl;
(b) xe2x80x94C5-7 alkyl optionally substituted with one or two substituents selected from 2-oxopyrrolidinyl, C1-3 alkylsuflonylamino, cyano, C1-3 alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, amino, C1-4 alkylamino, morpholinylcarbonyl, morpholino, C1-3alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl;
(c) xe2x80x94C1-4 alkyl substituted with one or two substituents selected from 2-oxopyrrolidinyl, C1-3 alkylsuflonylamino, cyano, C1-3 alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C1-3alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl; and
(d) C7-9 bicycloalkyl optionally substitued with di-C1-4 alkylamino and oxopyrrolidinyl;
R4 is thiazolyl, imidazolyl or oxazolyl, the thiazolyl, imidazolyl or oxazolyl being optionally substituted with one or two substituents independently selected from C1-4 alkyl and halo;
X is S, xe2x80x94NH, xe2x80x94Nxe2x80x94C1-4 alkyl or O;
R5 is hydrogen or C1-4 alkyl;
R6 is C1-4 alkyl or halo;
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4 or 5; and
p is 0, 1, 2, 3, 4, 5 or 6.
The 1,4-dihydropyridine compounds of this invention have excellent bradykinin antagonistic activity and are thus useful for the treatment of medical conditions caused by bradykinin such as inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis or the like in mammalian, especially humans.
The 1,4-dihydropyridine compounds of this invention have excellent bradykinin antagonistic activity and are thus useful for the treatment of medical conditions caused by bradykinin such as Amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, newrogenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching, Sepsis or the like in mammalian, especially humans.
The present invention provides a pharmaceutical composition for the treatment of disease conditions caused by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, bums, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis or the like, which comprises a therapeutically effective amount of the 1,4-dihydropyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Further, the present invention also provides a pharmaceutical composition for the treatment of Amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, newrogenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching or Sepsis, which comprises a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable carrier.
Also, the present invention provides a pharmaceutical formulation comprising a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients.
Also, the present invention provides a method for the treatment of disease conditions caused by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention provides a method for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, bums, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis or the like, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
As used herein, the term xe2x80x9chaloxe2x80x9d is fluoro, chloro, bromo or iodo.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, an example of xe2x80x9cC7-9 bicycloalkylxe2x80x9d means bicyclo[3.2.1]octyl, octahydropentalenyl, bicyclo[2.2.1]heptyl, and the like.
As used herein, an example of xe2x80x9cC3-7 cycloalkylxe2x80x9d means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
Preferred compounds of this invention are those of the formula (I) wherein
(A)n is 2,6-dichloro;
Y1 is xe2x80x94CH2xe2x80x94;
Y2 is N or CH;
R1 and R2 are independently methyl, ethyl or propyl;
R3 is selected from the following:
(a) xe2x80x94(CH2)pxe2x80x94C3-7 cycloalkyl, the cycloalkyl moiety being optionally substituted with one, two or three substituents selected from cyano, amino-C1-4 alkyl-, C1-4 alkylamino-C1-4 alkyl-, C1-3 alkyl-carbonylamino-C1-4 alkyl-, C1-4 alkylsulfonylamino-C1-4 alkyl, amino, 2-oxopyrrolidinyl, C4-7 cycloalkylamino-C1-4 alkyl, di-C1-4 alkylamino-C1-4 alkyl-, hydroxyl, carbamoyl, C1-3 alkylcarbonyl(C1-4 alkyl)amino, C1-4 alkylcarbonyl(C1-4 alkyl)amino-C1-4 alkyl, di-C1-4 alkylamino, pyrrolidinyl-C1-4 alkyl, 2-oxopyrrolidinyl-C1-4 alkyl and di-C1-4 alkylamino-C1-4 alkyl;
(b) xe2x80x94C5-7 alkyl optionally substituted with one or two substituents selected from 2-oxopyrrolidinyl, C1-3 alkylsuflonylamino, cyano, C1-3 alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, amino, C1-4 alkylamino, morpholinylcarbonyl, molipholino, C1-3 alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl; and
(c) xe2x80x94C1-4 alkyl substituted with one or two substituents selected from 2-oxopyrrolidinyl, C1-3 alkylsuflonylamino, cyano, C1-3 alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C1-3 alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl; and
(d) C7-9 bicycloalkyl optionally substitued with di-C1-4 alkylamino or oxopyrrolidinyl;
R4 is 1,3-thiazol-2-yl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, 1-ethyl-1H-imidazol-2-yl or 1,3-oxazol-2-yl;
X is S, -NH or -N-methyl;
R5 is hydrogen;
n is 2; and
p is 0, 1, 2, 3, 4, 5 or 6.
Much preferred compounds of this invention are those of the formula (I) wherein
R1 and R2 are methyl;
R3 is selected from the following:
(a) xe2x80x94(CH2)pxe2x80x94C4-6 cycloalkyl, the cycloalkyl moiety being optionally substituted with one or two substituents selected from cyano, amino-C1-4 alkyl-, C1-4 alkylamino-C1-4 alkyl-, C1-3 alkyl-carbonylamino-C1-4 alkyl-, C1-4 alkylsulfonylamino-C1-4 alkyl, amino, 2-oxopyrrolidinyl, C4-7 cycloalkylamino-C1-4 alkyl, di-C1-4 alkylamino-C1-4 alkyl-, hydroxyl, carbamoyl, C1-3 alkylcarbonyl(C1-4 alkyl)amino, C1-4 alkylcarbonyl(C1-4 alkyl)amino-C1-4 alkyl, di-C1-4 alkylamino, pyrrolidinyl-C1-4 alkyl, 2-oxopyrrolidinyl-C1-4 alkyl and di-C1-4 alkylamino-C1-4 alkyl;
(b) xe2x80x94C5-6 alkyl optionally substituted with one or two substituents selected from 2-oxopyrrolidinyl, C1-3 alkylsuflonylamino, cyano, C1-3 alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, amino, C1-4 alkylamino, morpholinylcarbonyl, morpholino, C1-3alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl;
(b) xe2x80x94C2-4 alkyl substituted with one or two substituents selected from 2-oxopyrrolidinyl, C1-3 alkylsuflonylamino, cyano, C1-3 alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C1-3 alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl; and
(d) bicyclo[3.2.1]octyl optionally substitued with C1-3 alkyl-amino or oxopyrrolidinyl;
R4 is 1,3-thiazol-2-yl, 1-methyl-1H-imidazol-2-yl or 1,3-oxazol-2-yl; and
p is 0, 1, 2 or 3.
Also, preferred compounds of this invention are those of the formula (I) wherein
R3 is selected from the following:
(a) (CH2)pxe2x80x94C4-6 cycloalkyl, the cycloalkyl moiety being optionally substituted with a substituent selected from cyano, aminomethyl, aminoethyl, ethylaminomethyl, methylaminoethyl, acetylaminomethyl, acetylaminoethyl, ethylcarbonylaminomethyl, methylsulfonylaminomethyl, methylsulfonylaminoethyl, amino, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, pyrrolidinylmethyl, pyrrolidinylethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, oxopyrrolidinyl, hydroxy, (ethyl)(acetyl)amino, (methyl)(acetyl)amino, (ethyl)(acetyl)aminomethyl, (methyl)(acetyl)aminomethyl, diethylamino, dimethylamino, aminocarbonyl and acetylaminomethyl;
(b) xe2x80x94C5-6 alkyl optionally substituted with a substituent selected from methylsulfonylamino, ethylsulfonylamino, cyano, acetylamino, ethylcarbonylamino, amino, etylamino, methylamino, oxopyrrolidinyl, 1,1-dioxoisothiazolidinyl, 2-oxo-1,3-oxazolidinyl, methyloxopyrrolidinyl, morpholinocarbonyl, morpholino, oxopiperidinyl and piperidinyl;
(c) xe2x80x94C2-4 alkyl substituted with a substituent selected from methylsulfonylamino, ethylsulfonylamino, cyano, acetylamino, ethylcarbonylamino, oxopyrrolidinyl, 1,1-dioxoisothiazolidinyl, 2-oxo-1,3-oxazolidinyl, methyloxopyrrolidinyl, morpholinocarbonyl, morpholino, oxopiperidinyl and piperidinyl; and
(d) bicyclo[3.2.1]octyl optionally substitued with methylamino, ethylamino or oxopyrrolidinyl.
Preferred individual compounds of this invention are:
dimethyl 2-[2-[4-[(1-cyanocyclohexyl)methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(ethylamino)methyl]cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[[1-[(acetylamino)methyl]cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[[(methylsulfonyl)amino]methyl]cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[(1-aminocyclohexyl)methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(ethylamino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(dimethylamino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(diethylamino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[[1-(1-pyrrolidinylmethyl)cyclopentyl]methyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[[1-[(cyclopentylamino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-(8-(diethylamino)bicyclo [3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[2,2-dimethyl-3-[(methylsulfonyl)amino]propyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[(1-cyanocyclopentyl)methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-(2-cyano-2-methylpropyl)-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[3-(acetylamino)-2,2-dimethylpropyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]- 1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[[1-(aminomethyl)cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-(3-amino-2,2-dimethylpropyl)-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-(ethylamino)-2,2-dimethylpropyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-methyl-3-(2-oxo-1-pyrrolidinyl)butyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[2,2-dimethyl-3-(2-oxo-1-pyrrolidinyl)propyl]-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[3-(2-oxo-1-pyrrolidinyl)propyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[4-(2-oxo-1-pyrrolidinyl)cyclohexyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-(1,1-dioxoisothiazolinyl)propyl]-1-piperadinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[3-(2-oxo-1,3-oxazolidin-3-yl)propyl]-1-piperadinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[[1-[(2-oxo-1-pyrrolidinyl)methyl]cyclohexyl]methyl-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[[1-[(2-oxo-1-pyrrolidinyl)methylcyclopentyl]methyl-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[2-(1-hydroxycyclohexyl)ethyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-(2-methyl-5-oxo-1-pyrrolidinyl)propyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-(3-methyl-2-oxo-1-pyrrolidinyl)propyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[3-[acetyl(ethyl)amino]propyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[-4-[[1-[(acetyl(ethyl)amino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[2-[1-(2-oxo-1-pyrrolidinylicyclopentyl]ethyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[2-[1-(diethylamino)cyclopentyl]ethyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-[4-[4-(2-oxo-1-pyrrolidinyl)butyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[4-methyl-4-(2-oxo-1-pyrrolidinyl)pentyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[2-[1-[2-oxo-1-pyrrolidinyl)methyl]cyclopentyl]ethyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-Dichlorophenyl)-2-[2-[4-[4-(4-morpholinyl)-4-oxobutyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[4-(4-morpholinyl)butyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-ethyl-3-(2-oxo-1-pyrrolidinyl)pentyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[2-[1-[(diethylamino)methyl]cyclopentyl]ethyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[4-(2-oxo-1-piperidinyl)butyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[4-(1-piperidinyl)butyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[2-[1-(aminocarbonyl)cyclopentyl]ethyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[1-[(acetylamino)methyl]cyclohexyl]-1-piperidinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[1-[(ethylamino)methyl]cyclohexyl]-1-piperidinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 2-[2-[4-[[1-(aminomethyl)cyclobutyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(ethylamino)methyl]cyclobutyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate; and
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[8-(2-oxo-1-pyrrolidinyl)bicyclo[3.2.1]oct-3-yl]-1-piperazinyl]carbonyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate.
Most preferred individual compounds of this invention are:
dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(dimethylamino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[[1-[(diethylamino)methyl]cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[[1-(1-pyrrolidinylmethyl)cyclopentyl]methyl]-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[3-methyl-3-(2-oxo-1-pyrrolidinyl)butyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[[1-[(2-oxo-1-pyrrolidinyl)methyl]cyclopentyl]methyl-1-piperazinyl]ethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[4-methyl-4-(2-oxo-1-pyrrolidinyl)pentyl]-1-piperazinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;
dimethyl 4-(2,6-dichlorophenyl)-2-[2-[4-[1-[(ethylamino)methyl]cyclohexyl]-1-piperidinyl]-2-oxoethyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate; and
dimethyl 4-(2,6-dichlorophenyl)-2-[2-oxo-2-[4-[8-(2-oxo-1-pyrrolidinyl)bicyclo[3.2.1]oct-3-yl]-1-piperazinyl]carbonyl]-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate.
The 1,4-dihydropyridine compounds of formula (I) of this invention may be prepared by a variety of synthetic methods known to those skilled in the art. For example, the 1,4-dihydropyridine compounds of formula (I), may be prepared by reaction of compound (II) with compound (III), followed, if desired, by conversion of a compound (III) in which R3 is H into a compound (III) in which R3 is other than H, as indicated in the following Preparation Method A. 
(wherein Z is hydrogen or lower alkyl (e.g., C1-4 alkyl) such as methyl and ethyl; and the other symbols are as already defined)
In Preparation Method A, when Z is lower alkyl, the compound (II) may be first subjected to selective saponification of the ester residue at the 2-position of the dihydropyridine ring, followed by acidification to afford a free acid, which is coupled with the compound (III) to give the 1,4-dihydropyridine (I). When Z is H, the compound (II) may be directly coupled with the compound (III) to obtain the 1,4-dihydropyridine (I).
The selective saponification and the acidification may be carried out by conventional procedures. In a typical procedure, the selective saponification is carried out by treatment with sodium hydroxide in a suitable reaction-inert solvent at a temperature in the range from xe2x88x9220 to 40xc2x0 C., usually from 10xc2x0 C. to 30xc2x0 C. for 3 minutes to 4 hours, usually 15 minutes to 1 hour. In a typical procedure, the acidification is carried out by treatment with diluted hydrochloric acid in a suitable reaction-inert solvent such as water at a temperature in the range from 0 to 30xc2x0 C., usually from 5xc2x0 C. to 25xc2x0 C. for 1 minute to 1 hour, usually 5 minutes to 15 minutes.
The 1,4-dihydropyridine (I) can be obtained from the corresponding 1,4-dihydropyridine (II) wherein R3 is H by a coupling reaction between the obtained acid and 4-N-substituted piperazine. The condensation may be carried out in a reaction-inert solvent, such as aqueous or non-aqueous organic solvents (e.g., tetrahydrofuran, dioxane, acetone, dimethoxyethane and acetonitrile); halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane) using a coupling agent such as dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate-triphenylphosphine, diethylcyanophosphonate (DEPC), diphenylphosphorylazide (DPPA) and ethyl chloroformate. This reaction may be carried out at a temperature in the range from xe2x88x9230 to 40xc2x0 C., usually from 0xc2x0 C. to 25xc2x0 C. for 10 minutes to 96 hours, usually 30 minutes to 24 hours.
In addition, when R3 is substituted-alkyl, the 4-N-substituted piperazines (III) as used herein may be either known or may be prepared by known methods. For example, the 4-N-substituted piperazines may be prepared by means of (1) N-alkylation of 1-N-protected piperazine with appropriate alkyl halide, R3-halo, (2) reductive amination of 1-N-protected piperazine with appropriate aldehyde or ketone in the presence of a reducing agent, followed by deprotection of the 1-N-protecting group, or (3) Michael addition of 1-N-protected piperazine with appropriate conjugated ketones, esters or amides, or (4) piperazine ring construction from N-substituted amine. Suitable 1-N-protecting groups include, for example, benzyl, benzyloxycarbonyl and t-butoxycarbonyl group.
The reductive alkylation may be carried out with appropriate aldehyde or ketone in a suitable reaction-inert solvent such as aqueous or non-aqueous organic solvents (e.g., tetrahydrofuran, dioxane, acetone, dimethoxyethane and acetonitrile); halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane), in the presence of a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxy borohydride at a temperature in the range from xe2x88x9220 to 120xc2x0 C., usually 0 to 80xc2x0 C. for 10 minutes to 1 week, usually 30 minutes to 96 hours, optionally in the presence of molecular sieves. Alternatively, alkylation can be made by two step synthesis. A ketone may be treated with an amine in an inert solvent such as toluene or xylene, at a temperature in the range from, 80 to 130xc2x0 C., usually 100 to 120xc2x0 C. for 10 hours to 2 week, usually 1 days to 1 week, preferably 3 to 5 days. The product may be reduced by hydrogenation in the presence of appropriate catalyst such as palladium on carbon and platinum oxide(IV), usually platinum oxide(IV) in an inert solvent such as ethanol and ethyl acetate, usually ethyl acetate, at a temperature in the range from 10 to 60xc2x0 C., usually 20 to 30xc2x0 C. for 1 hour to 3 days, usually 3 hours to 10 hours.
Typical Micheal addition reaction may be carried out at a temperature in the range from 30xc2x0 C. to 120xc2x0 C., usually from 60xc2x0 C. to 100xc2x0 C. for 5 hours to a week, usually 10 hours to 4 days. 
(wherein Z is lower alkyl such as methyl and ethyl; and the other symbols are as already defined)
This method utilizes the modified Hantzsch synthesis as described in A. Sausins and G. Duburs, Heterocycles, 1988, 27, 269. In this method, beta-keto ester (V) is first reacted with substituted benzaldehyde (VI) to obtain compound (VII). This reaction may be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, propanol and butanol; ethers such as diethyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as methylene dichloride, chloroform and dichloroethane; amides such as N,N-dimethylformamide; and nitrites such as acetonitrile. This reaction may be carried out at a temperature of 0xc2x0 C. to 200xc2x0 C., preferably from 80xc2x0 C. to 120xc2x0 C. for 30 minutes to 24 hours, preferably 30 minutes to 6 hours. If desired, this reaction may be catalyzed by a base such as piperidine, pyridine or alkoxide, or by an acid catalyst such as acetic acid, TiCl4 or p-toluenesulfonic acid.
Thereafter, the benzylidene (VII) as obtained above is reacted with enamine (VIII) in the presence of, or absence of a suitable condensing agent such as Lewis acids, to obtain the 1,4-dihydropyridine (II). This reaction may be carried out in the presence of, or absence of the reaction-inert solvent as listed above. However, this reaction may preferably carried out in the absence of a solvent. This reaction may be carried out at a temperature of 0xc2x0 C. to 200xc2x0 C., preferably, from 60xc2x0 C. to 150xc2x0 C. for 30 minutes to 48 hours, preferably 10 hours to 20 hours.
In addition, the beta-keto esters (V) which can be used herein may be prepared by known methods as shown in, for example: (1) J. Labelled Compds. Radiopharm., 1989, 27, 599; (2) J. Org. Chem., 1989, 54, 3258; (3) J. Am. Chem. Soc., 1974, 96, 1082; (4) J. C. S. Perkin I, 1979, 529; (5) Synthesis, 1986, 37; (6) J. C. S. Chem. Commun., 1977, 932, (7) Angew. Chem. Int. Ed. Engl., 1979, 18, 72 and (8) Tetrahedron Lett., 1983, 24, 5425. The benzaldehydes (VI) which can be used herein may be either already known or may be prepared according to the reported methods. 
(wherein all the symbols are as already defined)
This method utilizes the three components Hantzsch reaction. In a typical procedure, the beta-keto ester (V), the substituted benzealdehyde (VI) and the enamine (VII) may be heated together in a suitable reaction-inert solvent as listed above (preferably lower alkanols such as methanol and ethanol). Preferably, a small amount of a lower alkanoic acid such as acetic acid is added as catalyst. The reaction mixture may be heated at 80xc2x0 C. to 200xc2x0 C., preferably from 100xc2x0 C. to 140xc2x0 C. for 30 minutes to 1 week, usually 24 hours to 96 hours.
Preparation Method B-III
Compounds of formula (VIII) may be prepared by a process of this invention according to Scheme B-III. 
Scheme B-III exemplifies a process of this invention for preparing a compound of formula (II) comprising step (a): addition of an, enamine compound of formula (VIII) to an alkylene compound of formula (VII) followed by step (b) acid catalyzed cyclization reaction of the resulting compound in step (a).
The former addition step (a) may be carried out under conditions applied to nucleophilic addition reactions using a suitable base in a reaction inert solvent. More preferably, the reaction may be carried out under conditions commonly used in Michael-type addition. Preferred bases for this reaction are those used in Michael-type reactions. Examples of the preferred bases include alkylmagnesium halides known as Grignard reagents and halomagnesium alkoxides. More preferred bases include (C1-C6)alkylmagnesium bromide and tert-butoxy-magnesium bromide. Preferred solvents used in this reaction include (C1-C4)alkanol, tetrahydrofuran (THF), diethyl ether, dioxane, hexane, toluene, 1,2-dimethoxy ethane (DME) and the like. This reaction may be carried out at a temperature from about xe2x88x92150xc2x0 C. to reflux, preferably from about xe2x88x92100xc2x0 to 100xc2x0 C. In view of convenience, this reaction may be carried out at about room temperature using, for example, halomagnesium(C1-C4)alkoxides, (C1-C6)alkylmagnesiumhalides, metalhydrides, metal(C1-C3)alkoxides, magnesium-di[(C1-C3)alkoxides], metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide or a metalcarbonate such as K2CO3. In case of the base is K2CO3, the reaction is effectively run in THF. In case of the base is CsF or KF, the reaction is effectively run in THF or methanol (MeOH) at an elevated temperature such as at about 60xc2x0 C. In case of using butyllithium (BuLi), the reaction is effectively run in THF at from about xe2x88x9278xc2x0 to about xe2x88x9230xc2x0 C. In case of using halomagnesium(C1-C4)alkoxides or (C1-C6)alkylmagnesiumhalides, a preferred solvent is THF. Suitable reaction time ranges from about 3 minutes to about 2 days, preferably from about 30 minutes to about 40 hours.
The subsequent cyclization process step (b) may be carried out in the presence of a protonic acid. Suitable protonic acids include (C1-C6)alkanoic acid such as acetic acid, hydrochloric acid (HCl) and sulfonic acids such as p-toluenesulfonic acid. It is preferred to add a non-protonic Lewis acid to the reaction mixture in combination with the protonic acid, when the base used in Step (a) is other than magnesium (VIII) bases. This reaction may be carried out at a temperature from about xe2x88x92150xc2x0 C. to reflux, preferably from about xe2x88x92100xc2x0 to 100xc2x0 C. The reaction time ranges from about 1 second to 5 days, preferably 5 minutes to 20 houres.
Generally, those reactions illustrated in Scheme B-Ill may be carried out at about xe2x88x9278xc2x0 C. using dry-ice/acetone or dry-ice/methanol, about 0xc2x0 C. using an ice-bath, room temperature or 100xc2x0 C., preferably at about 0xc2x0 C. or about room temperature.
The reaction steps (a) and (b) are performed in the same reaction vessel under mild conditions with high-yield.
An enamine compound of formula (VIII) may be prepared according to procedures known to those skilled in the art, such as those illustrated in Scheme B-III-a. 
Typically, a beta-keto ester compound of formula (VIII-P) may be transformed to a compound of formula (VIII) wherein R2, R5 and Z are defined as above. This reduction may be carried out in a reaction inert solvent resolving ammonia gas at a temperature in the range of from about 0xc2x0 to 60xc2x0 C. Suitable reaction inert solvents include lower alkanols such as methanol and ethanol. Alternatively, an ammonia gas containing solution given above may be added to a solution containing a beta-keto ester (VIII-P). The mixture is reacted at a temperature in the range of from about 0xc2x0 to 60xc2x0 C. to yield the enamine compound (VIII).
An alkylene compound of formula (VII) may be prepared according to procedures known to those skilled in the art. Scheme B-III-b illustrates one embodiment of the preparation process. 
A carbonyl compound of formula (V) may be subjected to a coupling reaction with an aldehyde compound of formula (VI) to give the alkylene compound of formula (VII) according to a known procedure. For example, a compound of formula (V) may be reacted with a compound of formula (VI) according to a procedure reported by L. Tietze et al. Liebigs Ann. Chem., pp. 321-329, 1988. This reaction may be carried out in a suitable reaction inert-solvent for example an aromatic hydrocarbon such as benzene, toluene and xylene, an alcohol such as methanol, ethanol, propanol and butanol, an ether such as diethyl ether, dioxane and tetrahydrofuran (THF), a halogenated hydrocarbon such as methylene dichloride, chloroform and dichloroethane, an amide such as N,N-dimethylformamide, and a nitrile such as acetonitrile. This reaction may be carried out at a temperature in the range of from about 0xc2x0 C. to the reflux temperature of the reaction mixture, preferably from about 80xc2x0 to the 120xc2x0 C. for from about 30 minutes to 24 hours, preferably from 30 minutes to 6 hours. This reaction may conveniently be carried in the presence of a base or acid catalyst. Suitable base catalysts are such as piperidine, pyridine and alkoxide, and suitable acid catalysts are such as acetic acid, TiCl4 and p-toluenesulfonic acid.
An intermediate compound of formula (V) may be prepared starting from a known compound according to a procedure known to those skilled in the art. For example, a compound of formula (V) may be prepared according to the procedure described in Scheme B-III-c. 
An aldehyde compound (V-3), wherein R4 is defined as above, is reacted with malonic acid under a basic condition. For example, this reaction may be carried out in the presence of a weak base such as piperidine in a reaction inert solvent such as pyridine to give a carboxylic acid compound of formula (V-2). The compound (V-2) thus obtained may be subjected to an aliphatic nucleophilic substitution reaction in the presence of a coupling agent to give a pentenoate compound of formula (V-1). This reaction may conveniently be carried out first by treating the compound of formula (V-1) with a coupling agent such as N,Nxe2x80x2-carbonyldiimidazole in a reaction inert solvent such as dimethylformamide, then reacting with a neucleophilic reagent such as CH3O2CCH2K in the presence of a Lewis acid such as magnesium chloride. The former treatment may be carried out at a temperature in the range of from about 0xc2x0 to 60xc2x0 C., preferably at about room temperature for from about 1 minutes to 12 hours. The latter reaction may be carried out at the temperature in the range of from about 0xc2x0 to 100xc2x0 C., preferably from about room temperature to 60xc2x0 C. for from about 1 minutes to 12 hours. The compound of formula (V-1) may be reduced over a metal catalyst under hydrogen atmosphere to give the compound of formula (V) according to a known procedure. Suitable catalysts are such as Raney nickel catalyst and a noble metal catalysts including palladium on carbon and palladium hydroxide. This reaction may be carried out in a reaction inert solvent such as methanol, at about room temperature under hydrogen at an appropriate pressure for example using a balloon, for about 1 minutes to 12 hours.
A ketone compound of formula (V) and a substituted benzaldehyde compound of formula (VI) may also be prepared according to known procedures (e.g., (1) D. Scherling, J. Labelled Compds. Radiopharm., Vol. 27, pp. 599-, 1989, (2) C. R. Holmquist et al., J. Org. Chem., Vol. 54, pp. 3528-, 1989, (3) S. N. Huckin et al., J. Am. Chem. Soc., Vol. 96, pp. 1082-, 1974, (4) J. C. S. Perkin I, pp. 529-, 1979, (5) Synthesis pp. 37, 1986, and (6) J. C. S. Chem. Commun., pp. 932-, 1977). 
(wherein all the symbols are as already defined)
This method also utilizes the three components Hantzsch reaction as mentioned above. The reaction conditions similar to the above can be also used in this method.
The enamine (IX) may either be known compounds or may be prepared by known methods. For example, the enamine (IX) may be prepared by reacting the beta-keto ester (V) with ammonia. More specifically, the beta-keto ester (V) may be dissolved in a suitable solvent as listed above. Excess amount of ammonia gas is introduced into the solution at a temperature of 0 to 60xc2x0 C. Alternatively, a solution containing ammonia dissolved in the above solvent is added to the solution-containing the beta-keto ester (V), and the resultant mixture is reacted at a temperature of 0 to 60xc2x0 C., to obtain the enamine (IX).
The compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as recrystallization or chromatographic purification.
General Synthesis of the optical active 1,4-dihydropyridine
The optically active compounds of this invention can be prepared by several methods. For example, the optically active compounds of this invention may be obtained by chromatographic separation or fractional crystallization from the final compounds or the intermediates in racemic form thereof. Alternatively, the optically active compounds may be prepared by optically selective reaction, enzymatic hydrolysis or reactions using optically active intermediates.
For example, the optically active 1,4-dihydropyridine (I-o) may be prepared by reaction of the compound (II-o) with the compound (III), followed, if desired, by conversion of the compound (III) in which R3 is H into the compound (III) in which R3 is other than H, as indicated in the following Preparation Method A-o. 
(wherein Z is hydrogen or lower alkyl (e.g., C1-4 alkyl) such as methyl and ethyl; and the other symbols are as already defined)
In Preparation Method A-I, when Z is lower alkyl, the compound (II-o) may be first subjected to selective saponification of the ester residue at the 2-position of the dihydropyridine ring, followed by acidification to afford a free acid, which is coupled with the compound (III) to give the 1,4-dihydropyridine (I-o). When Z is H, the compound (II-o) may be directly coupled with the compound (III) to obtain the 1,4-dihydropyridine (I-o).
The selective saponification and the acidification may be carried out by conventional procedures. In a typical procedure, the selective saponification is carried out by treatment with sodium hydroxide in a suitable reaction-inert solvent at a temperature in the range from xe2x88x9220 to 40xc2x0 C., usually from 10xc2x0 C. to 30xc2x0 C. for 3 minutes to 4 hours, usually 15 minutes to 1 hour. In a typical procedure, the acidification is carried out by treatment with diluted hydrochloric acid in a suitable reaction-inert solvent such as water at a temperature in the range from 0 to 30xc2x0 C., usually from 5xc2x0 C. to 25xc2x0 C. for 1 minute to 1 hour, usually 5 minutes to 15 minutes.
A compound (I-o) can be obtained from the corresponding compound (II-o) wherein R3 is H by a coupling reaction between the obtained acid and 4-N-substituted piperazine. The condensation may be carried out in a reaction-inert solvent such as aqueous or non-aqueous organic solvents (e.g., tetrahydrofuran, dioxane, acetone, dimethoxyethane and acetonitrile); halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane) using a coupling agent such as dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate-triphenylphosphine, diethylcyanophosphonate (DEPC), diphenylphosphorylazide (DPPA) and ethyl chloroformate. This reaction may be carried out at a temperature in the range from xe2x88x9230 to 40xc2x0 C., usually from 0xc2x0 C. to 25xc2x0 C. for 10 minutes to 96 hours, usually 30 minutes to 24 hours.
In addition, when R3 is substituted-alkyl, the 4-N-substituted piperazines (III) as used herein may be either known or may be prepared by known methods. For example, the 4-N-substituted piperazines may be prepared by means of (1) N alkylation of 4-N-protected piperazine with appropriate alkyl halide, R3-halo, (2) reductive amination of 4-N-protected piperazine with appropriate aldehyde or ketone in the presence of a reducing agent, followed by deprotection of the amino-protecting group, or (3) Michael addition of 4-N-protected piperazine with appropriate conjugated ketone, ester or amide, or (4) piperazine ring construction from N-substituted amine. Suitable amino-protecting groups include, for example, benzyl, benzyloxycarbonyl and t-butoxycarbonyl group.
The reductive alkylation may be carried out with appropriate aldehyde or ketone in a suitable reaction-inert solvent such as aqueous or non-aqueous organic solvents (e.g., tetrahydrofuran, dioxane, acetone, dimethoxyethane and acetonitrile); halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane), in the presence of a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature in the range from xe2x88x9220 to 120xc2x0 C., usually 0 to 80xc2x0 C. for 10 minutes to 1 week, usually 30 minutes to 96 hours, optionally in the presence of molecular sieves. Alternatively, alkylation can be made by two step synthesis. A ketone may be treated with an amine in an inert solvent such as toluene or xylene, at a temperature in the range from 80 to 130xc2x0 C., usually 100 to 120xc2x0 C. for 10 hours to 2 week, usually 1 days to 1 week, preferably 3 to 5 days. The product may be reduced by hydrogenation in the presence of appropriate catalyst such as Palladium on carbon and platinum oxide (IV), usually platinum oxide in an inert solvent such as ethanol and ethyl acetate, usually ethyl acetate, at a temperature in the range from 10 to 60 xc2x0 C., usually 20 to 30xc2x0 C. for 1 hour to 3 days, usually 3 hours to 10 hours.
Typical Micheal addition reaction may be carried out at a temperature in the range from 30xc2x0 C. to 120xc2x0 C., usually from 60xc2x0 C. to 100xc2x0 C. for 5 hours to a week, usually 10 hours to 4 days.
The optically active intermediates of formula (II) can be prepared by the following methods. 
(wherein [B1 B2 B3]NH+ is a chiral amine residue; Z is hydrogen; R*COOH and R*SO3H are chiral acids and the other symbols are already defined.)
In this method, an acid compound (II-a) may be subjected to a fractional crystallization with a chiral amine such as cinchonidine, cinchonine, quinine, burcine and phenethylamine or their derivatives, amino acids to obtain an amine salt (II-b). This reaction may be conducted in an organic solvent, preferably a pure or mixed alcoholic solvent selected from methanol, ethanol, 2-propanol and mixture thereof. The resulted salt may be further purified by several times recrystallization. The pure salt thus obtained may be converted to the corresponding carboxylic acid (an enantiomer of compound (II) wherein Z is H) by a partition between organic solvent such as ethyl acetate or dichloromethane and acid solution such as diluted hydrochloric acid followed by concentration. On the other hand, the salt of the antipode contained in the resulted mother liquid may be converted to the corresponding carboxylic acid (an enantiomer of compound (II) wherein Z is H) by the same procedure descried above after concentration of the mother liquid. This acid may be further purified by crystallization in organic or inorganic solvents to give the antipode. This crystallization of the acid may be performed several times, if necessary, to improve its optical purity.
Furthermore, a final compound (I-a) may be resolved into each salt of both enantiomers by the same procedure described above using chiral acids such as tartaric acid and camphorsulfonic acids or their derivatives. The resolved salts thus obtained may be converted to the corresponding amines (each enantiomer of I-a) by a partition between organic solvent such as dichloromethane and basic solution such as aqueous sodium hydrogencarbonate or sodium hydroxide. 
(wherein Z1 is, for example, an acyloxymethyl group; and the other symbols are already defined.)
In this method, an ester compound (II-d) is subjected to enzymatic hydrolysis to obtain an optically active carboxylic acid (II-e) (Compound (II) wherein Z is H). Application of Lipase in 1,4-dihydropyridine for enantioselective hydrolysis is known in literature such as H. Ebiike, et. al., Tetrahedron Letters, 32, 5805 (1991). Suitable Z1 groups may include acyloxymethyl groups such as pivaloyloxymethyl and propionyloxymethyl. The enzymatic hydrolysis may be carried out in an aqueous organic solvent, preferably a water saturated ethereal solution such as isopropyl ether, t-butyl methyl ether or diethyl ether. This reaction may be carried out at a temperature from 0xc2x0 C. to 60xc2x0 C., preferably from 30xc2x0 C. to 45xc2x0 C. for 10 minutes to 4 weeks, preferably 1 days to 2 weeks.
Preparation Method B-IV-o (enantioselective Hantzsch cyclization)
The compound (II) may be obtained using enantioselective Hantzsch cyclization. This cyclization may be made by a condensation with either enone or enamine attached chiral auxiliaries or by condensation of the enone (VII) and the enamine (VIII) in the presence of chiral catalyst. The main literature (Tetrahedron .Lett,(1988),6437) precedent for this process involves the Enders SAMP/RAMP-methodology (chiral hydrazone tautomer of enamine). Other variants exists in the patent (Bayer""s DE 87/3714438 and DE 84/3423105) involving a chiral enamine formed from t-butylvaline.
The 1,4-dihydropyridine compounds of this invention possess an asymmetric center. Hence, the compounds can exist in separated (+)- and (xe2x88x92)-optically active forms, as well as in racemic one thereof. The present invention includes all such forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation in the preparation of the final product or its intermediate.
The present invention includes salt forms of the compounds (I) as obtained above.
Insofar as the 1,4-dihydropyridine compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned 1,4dihydropyridine base compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts can be prepared by conventional procedures.
The 1,4-dihydropyridine compounds of the present invention of formula (I) exhibit significant bradykinin receptor-binding activity and therefore, are of value in the treatment of a wide variety of clinical conditions in mammals, especially human. Such conditions include inflammation, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, bums, virus infection, head injury, multiple trauma and the like.
Therefore, these compounds are readily adapted to therapeutic use as bradykinin antagonists for the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
Also, the compounds of formula (I) are co-administered with H1-antagonist.
Further, the present invention also encompasses a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer""s disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, cystitis, pancreatitis, Amyotrophic lateral sclerosis, Huntington""s disease, Parkinson""s disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, newrogenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching, Sepsis or the like, which comprises a therapeutically effective amount of the 1,4-dihydropyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier and H1-antagonist.
The compounds of the invention may advantageously be employed in combination with one or more other therapeutic ingredients selected from an antibiotic, anti-fungal, or anti-viral agent, an anti-histamine, a non-steroidal anti-inflammatory drug or disease modifying anti-rheumatic drug.
The combination with an anti-histamine (H1 antagonist) is particularly favorured for use in the prophylaxis and treatment of asthma. Examples of anti-histamine are chlorpheniramine, brompheniramine, clemastine, ketotifen, azatadine, loratadine, terfenadine, cetirizine, astemizole, tazifylline, levocabastine, diphenhydramine, temelastine, etolotifen, acrivastine, azelastine, ebastine, mequitazine, KA-398, FK-613, mizolastine, MDL-103896, levocetirizine, mometasone furoate, DF-1111301, KC-11404, carebastine, ramatroban, desloratadine, noberastine, selenotifen, alinastine, E-4716, efletirizine, tritoqualine, norastemizole, ZCR-2060, WY-49051, KAA-276, VUF-K-9015, tagorizine, KC-11425, epinastine, MDL-28163 terfenadine, HSR-609, acrivastine and BMY-25368.
The activity of the 1,4-dihydropyridine compounds of the present invention, as bradykinin antagonists, is determined by their ability to inhibit the binding of bradykinin at its receptor sites in recombinant human bradykinin B2 receptor expressing CHO-K1 cells (from Receptor Biology, Inc.) employing radioactive ligands.
The bradykinin antagonist activity of the 1,4-dihydropyridine compounds is evaluated by using the standard assay procedure described in, for example, Baenziger N. L., Jong Y-J. I., Yocum S. A., Dalemar L. R., Wilhelm B., Vaurek R., Stewart J. M., Eur. J. Cell Biol., 1992, 58, 71-80. This method essentially involves determining the concentration of the individual compound required to reduce the amount of radiolabelled bradykinin ligands by 50% at their receptor sites in CHO-K1 cells, thereby affording characteristic IC50 values for each compound tested.
More specifically, the assay is carried out as follows. First, rat, guinea pig or monkey ileum tissues are minced and suspended in 25 mM piperazine-N,Nxe2x80x2-bis (2-ethanesulfonic acid (PIPES) buffer (pH 6.8) containing 0.1 mg/ml of soybean trypsin inhibitor. Then, the tissues are homogenized using a Polytron homogenizer at setting 7 for 30 seconds three times, and then rehomogenized with a Teflon-coated homogenizer. The homogenized suspension was centrifuged at 1,200xc3x97g for 15 minutes. The pellet was rehomogenized and then centrifuged at 1,200xc3x97g for 15 minutes. These supernatant were centrifuged at 10,000xc3x97g for 60 minutes. The tissue pellets, CHO-K1 cell membrane are suspended in 25 mM PIPES buffer (pH 6.8) containing 1.25 mM dithiothreitol, 1.75 xcexcg/ml bacitracin, 1 mM o-phenanthroline, 18.75 xcexcM captopril, 1.25 mg/ml bovine serum albumin (BSA), to prepare tissue/cell suspensions. Then, 10 xcexcl of test compound solution dissolved in phosphate buffered saline (PBS, pH 7.5) containing 2% DMSO (final) and 0.1% BSA (w/v) or 10 ml of 12.5 mM bradykinin in PBS (pH 7.5) containing 0.1% BSA (w/v) are placed in a reaction 96-well plate. 15 xcexcl of 8.3 nM [3H]bradykinin is added to the compound solution or bradykinin solution in the 96-well plate. Finally 100 xcexcl of the tissue or cell suspension are added to the mixture in the plate, and incubated at room temperature for 1 hour under the dark. After incubation, the resultant product in the reaction plates is filtered through 0.1% polyethylenimine presoaked LKB filermat. The filtrate is washed using a Skatron auto cell harvester. The tissue bound radioactivity is determined using a LKB betaplate counter. The IC50 value is determined using the equation:
Bound=Bmax/(1+[I]/IC50) 
wherein [I] means the concentration of the test compound.
All compounds prepared in the working examples as described below were tested by this method, and showed an IC50 value of 1 nM to 50 nM in CHO-K1 cells with respect to inhibition of binding at its receptor.
The bradykinin antagonist activity of the 1,4-dihydropyridine compounds in vivo is evaluated by a plasma leakage test. This test essentially involve determining the concentration of the individual compound required to reduce by 50% the amount of bradykinin-induced plasma leakage in rat urinary bladder, thereby affording characteristic ED50 values for each compounds tested.
More specifically, the assay is carried out as follows. 3.5-week old male Sprague-Dawlew rats are purchased from Charles River Japan Inc. The rats are fed on stock diet (CRF from Charles River Japan, Inc.) and maintained under the standard conditions (temperature, 23xc2x11xc2x0 C. and humidity 55xc2x15%) for at least 3 days. The rats are fasted overnight prior to the experiments. Each test group consists of 5 rats.
Bradykinin, purchased from Peptide Ins., is dissolved in the physiological saline (0.9% sodium chloride) at a concentration of 10 nmol/ml. The test 1,4-dihydropyridine compounds are dissolved or suspended at different concentrations in the physiological saline solution containing 10 mg/ml Evans blue (Wako Pure Chemical, Japan).
Captopril (5 mg/kg of body weight) is intraperitoneally (i.p.) injected to the rats, and 20 minutes later the rats are anesthetized by an administration of Nembutal (Abbott) (2.5 mg/kg of body weight). 5 minutes later, the test compound solution containing Evans blue is intravenously (i.v.) injected to the rats at a dose of 3 ml/kg of body weight. Another 5 minutes later, bradykinin is i.v. injected at a dose of 10 nmol/kg body weight. Thereafter, the rats are killed by dislocation of the neck and the urinary bladders are obtained. The urinary bladders are individually treated with 1 ml of formamide at 60xc2x0 C. for at least 16 hours to extract Evans blue from the tissue. The absorbency of the extract is measured spectrophotometrically at 605 nm to determine the dye concentration. The effect of the individual test compound is calculated as a percentage of the amount of Evans blue leaked into the urinary bladder as compared to the control (saline for the test compounds). Some compounds prepared in the working examples as described below exhibited a remarkable activity at a concentration of 0.2 mg/kg in the inhibition of urinary bladder leakage in this test system.
Human liver microsome assay
T1/2 value against human liver microsome was calculated by conventional procedure. More specifically, human liver microsomes (0.2 mg/ml) were mixed with 1 xcexcM of kinin B2 antagonist and incubated with in the presence of 1.3 mM NADP+, 0.9 mM NADH, 3.3 mM glucose-6-phosphate, 3.3 mM MgCl2, and glucose-6-phosphate dehydrogenase (8 units/ml) in a total volume of 1.2 ml of 100 mM potassium phosphate buffer, pH 7.4, at 37xc2x0 C. At specified incubation times (0, 5, 10, 30 minutes), an aliquot of 100 xcexcl was withdrawn from the reaction mixture and mixed with 1 ml of acetonitrile containing internal standard. Protein was precipitated by centrifugation at 1,800xc3x97g for 10 minutes, and the resulting supernatant was taken.
Kinin B2 antagonist in samples were analyzed by LS/MS/MS, in a Sciex API-300 mass spectrometer linked with a Hawlett-Pakkered HP1100 HPLC system. A sample of 20 xcexcl was injected to the HPLC system equipped with a Wakosil II 5C18 HG column (2.0xc3x97150 mm). The mobile phase consisted of 80% acetonitorile including 10 mM ammonium acetate, and the elution was isocratic with a flow rate of 0.3 ml/min. Part of the eluent from the HPLC column was introduced into the atmospheric ionization source via an ion spray interface. T1/2 value is determined using the equation:
T1/2=0.693/k 
wherein k is elimination rate constant of the test compound.
The compounds of the formula (I) exhibit excellent biological activity in vitro and in vivo as bradykinin antagonists. Additionally, the compound of the formula (I) was more stable against metabolism compared to structurally related 1,4-dihydropiridine disclosed in WO 96/06082 in human liver microsomes assay experiments. The most preferred compounds as memtined above of Working Examples showed T1/2 values of more than 20 minutes.
The 1,4-dihydropyridine compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 10 mg to 500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, for example, a dosage level that is in the range of from 0.06 mg to 2 mg per kg of body weight per day is most desirably employed for treatment of inflammation.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.